Studies of periodic catatonia — I

J. Psych&.

Res. Vol. 2, pp. 123-134. PergamonPress Ltd. Printedin Great Britain.

BLOOD

STUDIES

OF PERIODIC

LEVELS

OF PROTEIN-BOUND

EXCRETION

CATATONIA IODINE

OF VANILLYL-MANDELIC CLINICAL LEIV

Dikemark

R.

-

I

AND URINARY

ACID IN RELATION

TO

COURSE GJESSING

sykehus, Asker, Norway.

(Received 11 December

1962)

(Revised 1 October 1963)

GJESSING(~) has suggested that phasic variation in thyroid function may be involved in the clinical symptomatology of periodic catatonia. The variations between hypo- and hyperthyroid states which he found were not excessive as measured by oxygen consumption, the values remaining within the normal range. The administration of thyroid substance, but not dinitrophenol, appeared capable of producing a complete remission in this disorder. During spontaneous remission he reported that the basal metabolic rate returned to normal only after several months, while there was an early normalization of vegetative and psychic disturbances followed by normalization of the nitrogen excretion. Wishing to obtain more information about the thyroid function in 3 cases of periodic catatonia, we have studied the protein-bound iodine together with basal metabolic rate before, during and after loading with l-thyroxine and I-tri-iodo-thyronine. In order to get some information relative to the autonomic function in these patients, we also studied the excretion of the phenolic acids, especially the final excretory products of the catecholamines.

METHODS

Three patients with active periodic catatonia, one with periodic stupor and two with psycho-motor excitement attacks were investigated clinically over one year. Pulse rate, temperature, body weight, sleep and psychiatric evaluation were recorded daily. The psychiatric evaluation was subjectively carried out by the author on the basis of observing the patient daily, judging his power of concentration from l-5, where 1 represents the status between psychotic episodes and 5 deep stupor or extreme excitement as seen at the height of an exacerbation. Basal metabolic rate (BMR) was measured 3 times a week with a Krogh spirometer and protein-bound iodine (PBI) once a week with the method of Foss, et al.@) (Normal values: 4.0-S*O~g/lOOml of serum). Theexcretionpatternofphenolic 123

LEIV R. GJESSING

124

acids was studied daily in two cases over a period of 6 mth by the method of ARMSTRONG, et al.c3) We measured 3-methoxy-4-hydroxy-phenyl-acetic acid (HVA) and 3-methoxy-4hydroxy-mandelic acid (VMA). Subjective comparison of the unknown spots with authentic standards yielded an accuracy of f 10 per cent. Normal values for VMA : 1.5-3.0 pg per mg creatinine, and for HVA: 2.0-4.0 yg per mg creatinine. In addition hemoglobin (with’the cyanmeth-hemoglobin method(Q) as well as blood smears, leukocytes and sedimentation rate (SR) were examined 3 times a week in all 3 patients over 6 mth. Whenever urinary excretion was measured, the patients were placed on a standardized fluid diet consisting of milk, cream, eggs, sugar, vitamins, mineral salts, and water, excluding fruits and vegetables.

CASE Case I.

HISTORIES

Periodic catatonic stupor

E. L., born 1912, was admitted to this hospital in 1935.. The patient had 7 sisters and brothers. One brother was treated in a psychiatric clinic’in 1933 and one sister was admitted to a mental hospital in 1943. The patient was quite bright at school and reliable and efficient as a clerk. He was quiet and kind. In 1933 he changed in character and behavior. He became increasingly reserved, complained of fatigue and sleeplessness. He showed thinking difficulties and a bizarre mode of expression. Initiative, interests and activities decreased until he was completely inactive. When admitted to the hospital in 1935 he was fully oriented and said “his head was ruined”, that he was insensible and that his thoughts were conducted from the outside. He was autistic, empty, with decreased ability to concentrate, lacked spontaneity and had auditory hallucinations. During the following 6 yr his condition was unchanged. After 1941 he gradually showed irregular periods of days or weeks with psychomotor excitement while during the intervals he was in bed, autistic, unresponsive as before. From 1952 he had more regular periods with stupor lasting 3-4 wk and with intervals of similar duration. In the stupor, which might appear suddenly overnight, the patient lies in bed with his head above the pillow. Most of the time he is mute, motionless, and rigid with catalepsy. He is very negativistic and has to be fed, and sometimes his bladder has to be emptied by catheter. He is sleepless for a week or two. Temperature and especially pulse are elevated. Gradually he gets out of this condition, and one day he gets up, dresses nicely, eats and sleeps well and reads the newspapers. He is then smiling but very quiet and answers questions only with a few words. This patient has not been given any specific treatment like ECT, leukotomy or psychotropic drugs.

Case II.

Periodic catatonic excitement

K. H. Jo. was born in 1886. No known mental illness in the family, mediocre at school. Trained as a technician, had syphilis in 190.5, not specifically treated. Married in 1913, no children. He was pyknic and cyclic. In 1930 he gradually changed in behavior. He became more reserved, queer and restless, did not go to work, spoke to birds and dogs and said he could read the thoughts of cats. Admitted to this hospital in January 1932. Wassermann reaction in blood was slightly positive. Went through 2 stupor periods, each lasting about 10 days. Left hospital in December 1932. May-October 1937 readmitted because of a stupor period. Readmitted February-October 1938, but this time because of 4 periods of predominantly catatonic excitement. Last time readmitted May 1939. Since then the patient has had quite regular periods of catatonic excitement, belonging to the synchronous-syntonous type B,. c6) Both interval and psychotic phases last about 14 days. During the interval the patient is dressed and cleans his bed and room. He reads his newspaper and is well oriented, with intact memory. He is very co-operative in taking his fluid diet and collecting urine. But he is without interests or initiative and without insight.

STUDIES OF PERIODICCATATONIA - I

125

During the catatonic excited phase the patient starts to talk to himself in a self-constructed language. Gradually he gets more noisy, day and night, and he sings and talks continuously. He gets very restless, but he is oriented. His power of concentration is very poor. The maximum of the psychotic phase is reached within a week, then all signs and symptoms of excitement reverse within a week back to the interval level. This patient has not had any ECT. or leukotomy, but he was given 5 mg of reserpine daily per OS from April 1956 to February 1957. His periodic catatonic phases disappeared but his power of concentration remained lower than during his usual interval, and higher than during his catatonic phases. After withdrawal of reserpine it lasted approximately 4 mth before the catatonic phases reappeared. Otherwise this patient has not been treated with any psychotropic drugs.

FIG. 1.

Periodic catatonic stupor, CASE I.

This Fig. shows the changes between the catatonic phase and the interval with regard to the psychic state (power of concentration), temp., pulse, body weight, sleep, BMR, PBI, VMA, and HVA, before and during the load with 1-tri-iodo-thyronine-Na(T,), 0.02 mg increasing to 0.2 mg and later in varying amounts. Note the higb level of PBI and the decrease after the T,load as well as the elevated level of VMA in the psychotic phases.

aa42O40

-

+30 l *0+10%

Oii0

aI-

E

aa-

8

4-

; ‘i

m

a

z 8 ‘;

a214 13-

I

FIG. 2. Periodic catatonic stupor, CASE I. This Fig. is a continuation of Fig. 1 without VMA and HVA, but with hemoglobin (Hglb) and differential counts, leukocytes and sedimentation rate (SR). It shows the continuation of the T,-load and the spontaneous course after the load. Note the excellent corresponding values between BMR and PBI during the last period and the interval level of the PBI as well as the marked changes of the hemoglobin.

127

STUDIESOF PERIODICCATATONIA - I Case III.

Periodic catatonic excitement

E. R. 0~. was born in 1906. His father was an explosive psychopath who abused alcohol. His mother was anxious and nervous, but pyknic. He showed retarded development, started talking when 3 yr old. Rachitis. Working in electrical shop from his 15th to 26th year. He was a bit odd, contentious and reserved, with little drive. In 1932 he became sleepless and said that his head was heavy as lead and that his body was disintegrating. In January 1933 he suddenly got disturbed and violent and had to be admitted to a mental hospital (1933-35). During this time he had distinct periods of pronounced catatonic excitement lasting a few weeks, and intervals of nearly normal behavior, lasting 8-l 1 days. From 1935 to 1940 he was in a private nursing home, but since 1940 he has been in a mental hospital suffering from the same periodic disease, in spite of 160 electroshocks. The patient was admitted to this hospital in 1953. During these last 10 yr he had quite regular phases. In the intervals, lasting about 2-3 wk, he showed nearly normal behavior except for lack of insight. In the psychotic phase he was excited, violent, threatening, destructive, irritable and sleepless during the first two weeks, then gradually recovering during the following 2-3 wk back to the interval level. This patient has not had any specific treatment during the last 10 yr.

RESULTS

Case I

As can be seen in Fig. 1 and 2 this patient had regular phases of stupor from January to April 1961. He had a pronounced increase in pulse rate in the first part of the stupor phase. The body weight was stable during the first period except for an initial weight loss of approximately 4 kg due to the lower caloric value of the standard diet, but sleep was greatly disturbed during stupor. His BMR was elevated to about +20 per cent. during stupor and decreased to about -10 per cent. during the interval. The PBI was elevated above 10 pg/lOO ml in the stupor and went down to 7-8 pg/lOO ml in the interval. This high level may be due to the fact that all three of these patients got seaweed flour over a long period of time just prior to this investigation. The excretion of vanillyl-mandelic acid (VMA) was significantly increased during the stupor phase compared to the interval (p t0.001) (see Table 1, case I). The excretion of TABLE

1.

Case I

Case II

THE

VALUES ARE THE ARITHMETICAL MEANS f STANDARD (NUMBER OF ESTIMATIONS IN BRACKETS).

Phase

VMA pg/mg creatinine

Stupor Interval

4.1 f 0.5 (22) 2.0 f 0.3 (22)

PBI pg/lOO g serum 7.3 f 1.1 (7) 5.1 f 0.3 (7)

p<0Go1

p
4.7 f 0.6 (39) 3.8 f 0.6 (39)

6.2 f 0.7 (15) 5.2 f 0.4 (11) p <0.2

Excitement Interval

p
Case III

DEVIATION.

Excitement Interval

6.9 f 0.1 (4) 5.5 f 0.5 (4)

p


homovanillic acid (HVA) was slightly increased in the second and third stupor phases compared to the interval level, but remained within the normal limits. By loading with 1-tri-iodo-thyronine-Na(Ts) 0.02 mg in increasing doses to O-2 mg per OS,

128

LEIV R.

.K.H.J.l961 ',I

i2-

hrs

+,;:

J

110

Z,O

4.1

l/l

2/l

rq.1

yl

GJESSING

$0

Iyl

$0

21"

Y$

1p

2p

xl.1

1p

2fl

pp.'

'

B.M.R I/

3212501000ml

750500250Inn-

5.0-

1.25g

LOO0.7576,; 5.5 4z 3: " 2?4&

3-

=2l-

FIG.

3.

Periodic catatonic

excitement.

CASE II.

This Fig. illustrates the periodic changes of psychic state (ability to concentrate: upper curve), temp., pulse, body weight, sleep, BMR, PBI, diuresis, total N, creatinine, VMA, and HVA, before and during the load with 1-tri-iodo-thyronine-Na. Note the high level of PBI and the action of T, on PBI, as well as the elevated levels of VMA in each psychotic phase. At 1 urinary infection treated with sulfonamides, at 2 450 mg vit. C daily, at 3 irregular pulse treated with digitalis and 4 put on ordinary hospital diet.

1p

STUDIESOF PERIODICCATATONIA-

I

129

and later in varying amounts over a period of 43 mth, the BMR increased to about + 10 per cent. in the second interval, and up to about f50 per cent. in the stupor periods during the load and in the stupor period just after the load. The PBI decreased gradually to about 5 pg/lOO ml. The T3 did not affect the excretion of VMA or HVA either in the interval or in the stupor phase. The loading with Ta possibly prolonged the two intervals, but did not change the duration of the stupor phases significantly. After removal of T3 the BMR gradually became as before the load and PBI went up to about 8 pg/lOO ml in stupor and down to about 5 yg/lOO ml in the interval. The difference was significant (p tO.OO1) (see Table 1, case I). The normal values for PBI are 4.0-8.0 pg/lOO ml of serum. During the last 6 mth of 1961 there were pronounced changes in the hemoglobin value which seems to be a reflection of changes in extracellular space. The blood smears showed some periodic fluctuations and the leukocyte count was increased in two stupor phases. Sedimentation rate was usually below 10 mm/hr. Case II

As can be seen in Figs. 3 and 4, this patient had quite regular phases with slightly increased pulse rate and temperature during the excitement phases. Body weight was quite stable until the loading with Ta except for the initial weight loss of about 4 kg due to the caloric value of the standard diet. It then decreased until removal of Ta, when it climbed up to the initial weight. The sleep was always disturbed for a few days in each period. The BMR fluctuated from about -5 per cent. to -20 per cent. The Ta load increased the BMR above 0, but after the Ta load it fluctuated between 0 and -20. The PBI level was initially around 7 to 10 yg/lOO ml and decreased during the Ta load to below 3 pg/lOO ml. After this load it fluctuated between 5 and 7 pg/lOO ml. The diuresis and the total N fluctuated, but the creatinine values were quite stable. The VMA was markedly elevated in the excitement phase, up to around 6 pg, and it was also slightly elevated in the interval. The difference between the means of these two phases was found to be highly significant. (See Table 1, case II.) The normal range is 1.5-3.0 pg per mg creatinine. The HVA also showed periodic changes, but these were within normal limits. At 1 in Fig. 3, the patient had a urinary infection with increased Sedimentation Rate(SR) of 35 mm/hr. He was treated with sulfonamides and the SR went down to 4 mm/hr. From 2 in Fig. 2, the patient received 450 mg of vitamin C daily. At 3 the pulse rate became irregular so Ts was stopped and the patient was given digitalis for 5 days. From 4 on the patient was no longer given the standard diet but ordinary hospital diet. The blood smears, hemoglobin and leukocytes did not show marked changes during the different phases. The SR was predominantly below 10 mm per hour.

30 <

I-

x

5-

5

j

V

j

~ 1

P.6.I.

/ I

/--y/-%

5,’

=h 4-

50-

i

i

-

B-

.*c.

I

___j__

i

______

/

FIG. 4. Periodic catatonic excitement, CASE II. This Fig. is a continuation of Fig. 3, without urine constituents but with hemoglobin (Hglb), blood smears, leukocytes and sedimentation rate (SR). Note the interval level of PBI and the lack of pronounced hemoglobin changes.

FIG. 5.

Periodic catatonic excitement.

CASE III.

This Fig. illustrates the clinical changes as well as the BMR and the PBI before, during and after the load with 1-thyroxine-Na (T4) 0.1-l .O mgper OS. Note the weight changes with and without diet as well as the normal PBI level after the T, load.

t; c

132

LEIV R. GJESSING

Case III As can be seen in Fig. 5, this patient had quite regular periods with only small weight changes when on standard fluid diet (H-diet) but had more pronounced changes on ordinary diet. The pulse rate was elevated during the excitement phases but the temperature showed no pronounced changes. The sleep was regularly disturbed. The BMR varied between -20 and +20 per cent. and PBI between 7 and 10 pg. During I-thyroxine-Na(T4) load BMR tient up to +50 per cent., and PBI to 20 pg, and the length of the total period was increased. After withdrawing the Tq, the PBI went down to 5 pg/lOO ml and remained between 5 and 7 pg/lOO ml whereas the BMR decreased to +lO per cent. and remained between 0 and $20 per cent. The sedimentation rate was normal, below 5 mm/hr the whole year, except for a little peak to 20 mm during the initial part of the ,Tg load.

DISCUSSION

The clinical course of these three patients is typical for periodic catatonia,(@ with pronounced psychic changes, as well as increased pulse rate and temperature during active phases, weight changes and disturbed sleep periods. Case I is of the type A, Case II is type B, and Case III is type C according to the classification of R. GJBSSING.(@ The variations in BMR during active phases and intervals are also characteristic, but the level of PBI before loading seems to be higher than expected. This may be due to the fact that all three of these patients were given 20 g each of seaweed flour as an extra iodine supply, from 1956 until the middle of January 1961. After the Ts or T4 load the level of PBI seems to be normal, and the values for PBI and BMR seem to correspond better to each other. The load of T3 markedly lowered the level of PBI, from S-10 to 4 pg/lOO ml in Case I and from 7-9 to 2.5 pg/lOO ml in Case II. Concomitantly the levels of the BMR increased to above 50 per cent. during the stupor in Case I and above 20 per cent. in Case II. How normal these responses are is difficult to say, but by comparing them with similar investigations of FAURBYE, MUNKVAD and PIND, they seem to indicate a rather normal response.(7) The load of Tb to Case III increased PBI to above 20 pg and BMR to above $50 per cent. and seemed to be an adequate response to the doses administered. From these findings it is reasonable to assume that the reaction of these three patients to T3 and Tb loads was in line with a normal response. Regarding a probable specific action of these loads on the clinical course of this disease, it has to be emphasized that all 3 patients got these loads during their period of N-retention in which GJESSING has shown that thyroxine does not work. These loads were not given for treatment, but only for studying their action. After the loads the PBI and the BMR correspond very well to each other in all 3 cases. During the interval the values of PBI are about 5 pg, a little below the average normal value which is 6 pg. During the psychotic phases the PBI values are about 7-8 ,ug, which

STUDIES OFPERIODIC CATATONIA - I

133

is a little above the average normal value. These findings correspond very well to the statement of GJESSING,“~~~~the variations in thyroid function are not excessive, but within the normal range”.@) The excretion of VMA indicates that the activity of the sympathetic nervous system is probably operating normally during the interval but that the activity is strongly increased during the psychotic attack. These findings also support the clinical statement of GJESSINGabout the vegetative dynamics of these patients.@) In other words our measurements of PBI and VMA confirm earlier investigations, but do not help us in understanding why thyroid substance can produce complete compensation in this disease, or why this periodic disorder can persist over decades without thyroid treatment. A simple hypothetical explanation would be that a toxic substance is produced in the body of these patients and accumulates gradually until reaching a critical level. Then it may affect the hypothalamus which would discharge large amounts of amines, stimulate slightly the thyroid activity, and precipitate the psychotic phase. The adrenergically changed metabolism may gradually break down the toxic substance and the patient passes into a quiet interval. With the administration of thyroid substance and the consequent elevation of oxygen consumption, the toxic substance may also be detoxified sufficiently to keep the patient free from new attacks. We are continuing studying these patients, looking for this (or these) toxic endogenous substance(s) or its (their) breakdown products on the assumption that periodic catatonia is mainly a metabolic disease. SUMMARY (1) Three periodic catatonic patients were clinically investigated over a period of 1 yr. In order to obtain more information about the thyroid function we studied protein-bound iodine once a week and BMR 3 times a week, before, during and after loads of l-thyroxine and I-tri-iodo-thyronine. To obtain more information about the sympathetic nervous system we also measured the excretion of the final products of the catecholamine metabolism. (2) The response to the thyroxine and the tri-iodo-thyronine loads in these three patients, measured by oxygen consumption and protein-bound iodine, seems to be quite normal. (3) The level of protein-bound iodine corresponds well to oxygen consumption after these loads and both the PBI and BMR were slightly below the normal mean during the interval and slightly elevated during the psychotic attack, but all values were within the normal range (in accordance with earlier investigation by GJESSING). (4) The excretion of vanillyl-mandelic acid was mainly within the normal range during the interval, but was markedly elevated during the psychotic attack. This finding is taken as a sign of increased activity of the sympathetic nervous system during the psychotic phase (also in accordance with GJESSING’S earlier investigation). (5) Our results do not help us to understand the pathogenesis of this disease or the beneficial effects upon it of thyroid substance. (6) A simple hypothesis involving an endogenous toxic substance is put forward.

134

LEIV R. Gmm~

Acknowledgments.I wish to thank Dr. 0. P. Foss, for his assistance in carrying out the PBI analyses and Prof. A. FGLLING for valuable criticism and encouragement as well as H. BERG. A. FRENNINGSMOEN. N. H~VERSLAND,R. LANGSETH,G. LUNDEand C. A. SCHULTZfor their excellent technica assistance. ’ This work was in part supported by Research Grant M-5726, National Institute of Mental Health, United States Public Health Service.

REFERENCES 1.

GJESSING, R. Beitrage zur Somatologie der periodischen Befunde II. Arch. Psychiat. Nervenkr., 191, 297, 1953.

2.

Foss, 0. P., HANKES,L. V. and VAN SLYKE,D. D. A Study of the Alkaline Ashing Method for Determination of Protein-Bound Iodine in Serum. Clin. Chim. Acta., 5, 301-326, 1960.

3.

ARMSTRONG,M. D., SHAW, K. N. F. and WALL, P. E. The Phenolic Acids of Human Urine. J. Biol. Chem., 218,293-303, 1956.

4.

SCOTT,D., KNUDSEN,K. and KVAMME,E. Standardized HemogIobinometry. Tidsskr.f. D. N. Lagefor., 1960. GJESSING, R. and GJESSING,L. Some Main Trends in the Clinical Aspects of Periodic Catatonia. Acta psych. &and., 37:1, l-13, 1961. GJESSING, R. Beitrage zur Somatoiogie der periodischen Katatonie. V. Mitteilung. Verlaufstypen J3. Arch. Psychiat. Nervenkr., 191, 191-219, 1953. FAGBYE, A., MUNKVAD,I. and PIND, K. The Thyroid Function in Chronic Schizophrenia (Hebephrenia). Acta Endocrin., 28, 395409, 1958. 20, 980-982,

5. 6. 7.

Katatonie.

VIII.

Mitteilung.

Wertung der